Phosphoinositide 3-kinases (PI3-Ks) catalyze the synthesis of the phosphatidylinositol (PI) second messengers PI(3)P, PI(3,4)P2, and PI(3,4,5)P3 (PIP3). (Fruman et al., Phosphoinositide kinases, Annu. Rev. Biochem. 67 (1998), pp. 481-507; Knight et al., A Pharmacological Map of the PI3-K Family Defines a Role for p110α in Insulin Signaling, Cell 125 (2006), pp. 733-747.) In the appropriate cellular context, these three lipids control diverse physiological processes including cell growth, survival, differentiation, and chemotaxis. (Katso et al., Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer, Annu. Rev. Cell Dev. Biol. 17 (2001), pp. 615-675.) The PI3-K family comprises at least 15 different enzymes, sub-classified by structural homology, with distinct substrate specificities, expression patterns, and modes of regulation. The main PI3-kinase isoform in cancer is the Class I PI3-Kα, consisting of catalytic (p110α) and adapter (p85) subunits. (Stirdivant et al., Cloning and mutagenesis of the p110αsubunit of human phosphoinositide 3′-hydroxykinase, Bioorg. Med. Chem. 5 (1997), pp. 65-74.)
The 3-phosphorylated phospholipids (PIP3s) generated by PI3-Ks act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). (Vivanco & Sawyers, The Phosphatidylinositol 3-Kinase-Akt Pathway In Human Cancer, Nature Reviews Cancer 2 (2002), pp. 489-501.) Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, bringing Akt into contact with PDK1, which is responsible for activating Akt. The tumour-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-Ks, Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation. Several components of the PI3-K/Akt/PTEN pathway are implicated in oncogenesis. In addition to growth factor receptor tyrosine kinases, integrin-dependent cell adhesion and G-protein coupled receptors activate PI3-K both directly and indirectly through adaptor molecules. Functional loss of PTEN (the most commonly mutated tumour-suppressor gene in cancer after p53), oncogenic mutations in the PIK3CA gene encoding PI3-Kα, amplification of the PIK3CA gene and overexpression of Akt have been established in many malignancies. (see, for example, Samuels, et al., High frequency of mutations of the PIK3CA gene in human cancers, Science 304 (2004), p. 554; Broderick et al., Mutations in PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas, Cancer Research 64 (2004), pp. 5048-5050.)
PI3-Kα is thus an attractive target for cancer drug development since such agents would be expected to inhibit proliferation and surmount resistance to cytotoxic agents in cancer cells. There is a need to provide new PI3-Kα inhibitors that are good drug candidates. They should be bioavailable, be metabolically stable and possess favorable pharmacokinetic properties.